For 30 years, the tumor suppressor p53 has been a subject of intense research in nearly every discipline of scientific inquiry. While numerous surprising roles for p53 in health and disease are uncovered each year, the central role of its activation in preventing neoplastic transformation has been and will remain at the forefront of p53 research as investigators work to address an unexpectedly complex question—precisely how does p53 integrate upstream stress signals to coordinate activation of its target genes in response to stress? One manner in which to address this question is at the level of transcription initiation—after upstream signals converge on p53 and produce a number of pools of post-transcriptionally modified p53, how exactly are specific target promoters activated in such a sensitive, context-specific manner? The work presented herein aims to address the role of histone acetylation at the p21 promoter—a critical mediator of G1/S arrest—by the P/CAF acetyltransferase in response to a variety of p53-activating stresses. We show that depletion of P/CAF strongly inhibits p21 expression in response to a variety of stresses, despite normal stabilization of p53 and recruitment to target promoters. This defect in p21 expression correlates closely with abrogation of stress-induced cell-cycle arrest. Strikingly, a p53 allele lacking putative P/CAF acetylation sites was still able to direct p21 expression, which was still dependent upon P/CAF. We show further that histone acetylation at H3K14 at the p21 promoter following stress is dependent upon P/CAF. Rescue of p21 expression with wild-type P/CAF or a ∆HAT point mutant indicates that P/CAF requires an intact HAT domain, suggesting that histone acetylation at H3K14 is catalyzed by P/CAF HAT activity, not the molecular bridging of a heterologous HAT by P/CAF. Furthermore, RNA polymerase II (RNAP II) was present at the p21 proximal promoter under all basal and stress conditions, but elongation of RNAP II after stress required the presence of P/CAF. These data indicate that H3K14 acetylation by P/CAF closely correlates with the activation status of the p21 promoter, and may be necessary for activation of a larger subset of p53-responsive promoters. In addition to its critical role in p21 expression, we noted that p53 stabilization and cell-cycle arrest in response to p14ARF, but not other p53-stabilizing stresses, were also dependent on P/CAF. Cell-cycle arrest induced by p16INK4A was intact after P/CAF ablation, indicating a role for P/CAF in cell-cycle arrest specific to p14ARF-p53 signaling. Basal MDM2 levels were unaffected by P/CAF knockdown, as were p53- MDM2 and ARF-MDM2 complexes. A preliminary analysis of MDM2 localization was inconclusive, due to vastly different quantities of MDM2 in different conditions making analysis of subcellular localization difficult; however, the role of P/CAF in the relocalization of MDM2 to the nucleolus by p14ARF could potentially explain the defect in p53 stabilization, and should be explored further. These observations, underscored by recent reports that P/CAF undergoes loss of heterozygosity in several tumor types, suggest that P/CAF plays a critical role in p53-mediated cell-cycle arrest through multiple, independent mechanisms. Further study should clarify whether P/CAF is lost in tumors maintaining wild-type p53, and whether its reintroduction into these tumors confers any potential therapeutic benefit.

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Individuals who suffer from severe motor disabilities face the possibility of the loss of speech. A Brain-Computer Interface (BCI) can provide a means for communication through non-muscular control. Current BCI systems use characters that flash from gray to white (GW), making adjacent character difficult to distinguish from the target. The current study implements two types of color stimulus (grey to color [GC] and color intensification [CI]) and I hypotheses that color stimuli will; (1) reduce distraction of nontargets (2) enhance target response (3) reduce eye strain. Online results (n=21) show that GC has increased information transfer rate over CI. Mean amplitude revealed that GC had earlier positive latency than GW and greater negative amplitude than CI, suggesting a faster perceptual process for GC. Offline performance of individual optimal channels revealed significant improvement over online standardized channels. Results suggest the importance of a color stimulus for enhanced response and ease of use.

Previous studies have found that behavioral and P300 responses to speech are influenced by linguistic cues in the stimuli. Research has found conflicting data regarding the influence of phonemic characteristics of stimuli in the mismatch negativity (MMN) response. The current investigation is a replication of the study designed by Tampas et al. (2005), which studied the effects of linguistic cues on the MMN response. This current study was designed to determine whether the MMN response is influenced by phonetic or purely acoustic stimuli, and to expand our knowledge of the scalp distribution of processing responses to within- and across-category speech and nonspeech stimuli. The stimuli used in this study consisted of within-category synthetic speech stimuli and corresponding nonspeech frequency glides. Participants consisted of 21 (11 male and 10 female) adults between the ages of 18 and 30 years. A same/different discrimination task was administered to all participants. Data from behavioral responses and event-related potentials (MMN and P300) were recorded. Results provided additional evidence that the MMN response is influenced by linguistic information. MMN responses elicited by the nonspeech contrasts had more negative peak amplitudes and longer latencies than MMN responses elicited by speech contrasts. Brain maps of t scores for speech vs. nonspeech contrasts showed significant differences in areas of cognitive processing for all contrast pairs over the left hemisphere near the temporal and parietal areas. The present investigation confirms that there are significant differences in the cortical processing of speech sounds vs. nonspeech sounds.

Moderate-to-severe traumatic brain injury (M/S TBI) can affect an individual's ability to perform daily tasks. For example, individuals with M/S TBI are more likely to commit errors on tasks such as making a meal or wrapping a present. The neural processes involved in such errors are poorly understood. Studies suggest that neurophysiologic markers of cognitive control and error processing may be helpful in gaining additional insight into errors on naturalistic action tasks. Unfortunately, previous experimental methods left a methodological gap which limited the use of neurophysiological markers in the study of naturalistic action. Several recent studies in healthy adults have suggested one method of bridging the gap by having individuals observe another person's errors. The current study was the first study to employ the method in a TBI population as a possible means of gaining additional insight into the detrimental effects of M/S TBI on the performance of naturalistic actions. In order to gain additional insight into the effects of M/S TBI on the completion of naturalistic tasks I used two neurophysiologic markers of cognitive control and error processing. They were the observer error related negativity (oERN) and the P300 components of the scalp-recorded event-related potential (ERP). I hypothesized that individuals with M/S TBI would demonstrate error-specific changes in the two oERN and P300 that would correlate with self-reported difficulties in daily functioning. The study consisted of two experiments. One compared 15 individuals with M/S TBI to 17 demographically similar healthy controls on an error related naturalistic action based picture task. The second compared an overlapping sample of 16 individuals with M/S TBI to 16 demographically similar controls as they watched a confederate complete the Erikson flanker task, a commonly used task in the study of electrophysiological markers. Accuracy (error vs. correct) and group (M/S TBI vs. control) effects were analyzed using 2 x 2 repeated measures ANOVAs on ERP amplitude and latency. Pearson product-moment correlations were calculated to evaluate the relationship between the P300 and oERN and measures of self-reported executive functioning (Frontal Systems Behavior Scale, FrSBe) and neuropsychological measures. Findings supported a difference between the control and M/S TBI groups in how errors were processed during the naturalistic actions based picture task. There was an interaction between group membership and response accuracy (error vs. correct) on P300 amplitude and P300 latency. Controls demonstrated reduced P300 amplitude and latency on error trials compared to correct trials. Individuals with M/S TBI did not demonstrate a significant difference between correct trials and error trials on P300 amplitude and latency. The amplitude and latency of the P300 were correlated with self-reported functional difficulties in individuals with M/S TBI but not control participants. A Fisher's r -- z analysis indicated that correlations differed significantly between groups; however, an outlier was identified in the correlational data. Removal of the outlier data led to non-significant results in the Fisher's r -- z analysis. Taken together, results of the picture task supplied evidence that for individuals with M/S TBI differences in neurophysiologic markers between groups could be explained by reduced adaptation to complexity or by possible deficits in a secondary error processing pathway for complex errors. Future research could focus on better defining the functional relationship between P300 amplitude and latency and increased errors in naturalistic actions following M/S TBI. Observation of the flanker task did not elicit oERN waveforms from either healthy controls or from individuals with M/S TBI. The results could be due to problems with the current task, but also raised some concerns about previous studies using the flanker task which employed a slightly different methodology requiring participants to count errors. The current study did not require participant to count errors. As a whole, the study supplied partial support for using electrophysiological markers of error processing to gain additional understanding increased errors in the performance of naturalistic actions following M/S TBI.

Durant l'envelliment es dónen canvis estructurals i funcionals al cervell, especialment a l'escorça prefrontal, un dels substractes anatòmics responsables del control atencional. Aquest es va mesurar emprant tècniques neuropsicològioques i neurofuncionals durant l'execució de tasques de canvi amb senyals implícites (tipus WCST). 80 subjectes majors sans es varen dividir segons la seva edat i el seu nivell de control cognitiu. El baix control cognitiu (però no l'edat) s'associà a un augment dels costos residuals de resposta, en paral.lel amb una major amplitud del component P2 davant els senyals. L'edad avançada, en conjunt amb un baix nivell de control s'associà a un increment dels costos locals de resposta durant el canvi de tasca, paral.lelament amb l'augment de les ones lentes durant la fase de senyalització. Mantenir dues tasques en memòria es més difícil per als subectes amb baix control, reflexat per una reducció en l'amplitud de les ones lentes fronto-parietals

Des sons émotionnels furent présentés comme stimuli cibles lors d'une tâche auditive de type oddball. Les effets acoustiques furent départagés des effets émotionnels à l'aide d'une tâche contrôle similaire utilisant une version brouillée des sons originaux et dépourvue de propriétés émotionnelles. Les résultats du oddball émotionnel qui ont différé du oddball contrôle ont montré des effets de valence inversés dans les composantes électrophysiologiques P2 et P300; la valence négative ayant une amplitude plus grande dans la fenêtre de 130-270ms mais moins intense autour de 290-460ms, lorsque comparée aux valences positives et neutres. Les résultats P2 peuvent être interprétés comme une mobilisation attentionnelle précoce privilégiant les stimuli potentiellement dangereux, tandis que les résultats de la P300 pourrait indiquer une évaluation moins détaillée de ces stimuli. / In an auditory oddball task, negatively (disgust) and positively (laughter) valenced sounds were presented as rare targets. To disentangle acoustic effects from emotional ones, a control oddball was conceived with a non‐emotional scrambled version of the original target sounds as rare targets. Results from the emotional oddball that differed from the control oddball showed an inverse effect of valence in the P2 and P300 range, with negative valence having higher mean amplitude values in the 130‐270ms range, but lower values in the 290‐460 range when compared to ERPs elicited by positive and neutral valence. The P2 results are interpreted as early mobilization of attentional resources towards potentially threatening stimuli, while the P300 results could reflect less detailed evaluation of such stimuli.

La chaise roulante contrôlée par ondes cérébrales développée dans le cadre de cette thèse, et ci-après nommée BCW pour "Brain Controlled Wheelchair", est un système robotique pour les personnes qui, comme celles victimes d'un "locked-in syndrom", n'ont pas la capacité d'utiliser une interface conventionnelle. Notre but est de développer un système utilisable dans les hôpitaux et aux domiciles des utilisateurs, avec un minimum de modifications des infrastructures, pour les aider à récupérer un peu de mobilité. La difficulté principale est de contrôler de manière continue et précise les mouvements de la chaise roulante à partir d'une interface cerveau machine, typiquement très limitée en terme de taux de transfert de l'information. Par ailleurs, nous imposons que notre système soit sécuritaire, ergonomique et relativement bon marché. Notre stratégie repose sur 1) contraindre les déplacements de la chaise roulante le long de chemins virtuels prédéfinis, et 2) une interface cerveau machine lente mais précise, basée sur le signal P300, pour sélectionner la destination dans un menu. Cette stratégie réduit le contrôle à la sélection de la destination désirée, et donc ne nécessite que très peu d'effort de concentration de la part de l'utilisateur. Par ailleurs, la trajectoire est prévisible, ce qui contribue à réduire le stress et la frustration induits par des trajectoires générées par un agent artificiel. Nous proposons deux interfaces rapides pour permettre d'arrêter la chaise roulante en cours de déplacement. Nous avons développé une interface hybride qui combine l'interface P300 lente utilisée pour sélectionner la destination, avec une des deux interfaces rapides pour arrêter la chaise. Nous avons conduit des expériences avec des sujets non handicapés, et nous avons montré que, après une courte phase de calibration, il était possible de sélectionner une destination en 15 secondes en moyenne, avec un taux d'erreur de moins de 1%. Les interfaces rapides quant à elles permettent d'arrêter la chaise en moins de 5 secondes en moyenne. Par ailleurs, nous avons constaté que les performances de l'interface restaient égales en mouvement et à l'arrêt. Finalement, nous avons évalué notre stratégie et comparé avec les autres projets de chaise roulantes contrôlées par ondes cérébrales. Malgré le délai requis pour sélectionner une destination sur notre interface, notre chaise est plus rapide que les autres (36% plus rapide que MAIA): grâce à notre contrôle de trajectoire, notre chaise suit toujours le chemin le plus court et il est possible d'autoriser une plus grande vitesse sans compromettre la sécurité de l'utilisateur. Nous avons également comparé en utilisant une fonction de cout qui prends en compte le temps de trajet et l'effort de concentration requis; le cout de notre stratégie est de loin le plus bas (le meilleur autre score est 72% plus grand). Le résultat de ce projet est une chaise roulante contrôlée par ondes cérébrales, entièrement originale et fonctionnelle, qui permet de se déplacer dans un environnement connu en un temps raisonnable. L'accent a été mis sur la sécurité et le confort de l'utilisateur: le contrôle de trajectoire garanti une trajectoire régulière, sans heurts et prévisible, cependant que l'effort mental et minimisé par la réduction du pilotage à la sélection de la destination.

In this study, a P300 based Brain-Computer Interface (BCI) system design is realized by the implementation of the Spelling Paradigm. The main challenge in these systems is to improve the speed of the prediction mechanisms by the application of different signal processing and pattern classification techniques in BCI problems. The thesis study includes the design and implementation of a 10 channel Electroencephalographic (EEG) data acquisition system to be practically used in BCI applications. The electrical measurements are realized with active electrodes for continuous EEG recording. The data is transferred via USB so that the device can be operated by any computer. v Wiener filtering is applied to P300 Speller as a signal enhancement tool for the first time in the literature. With this method, the optimum temporal frequency bands for user specific P300 responses are determined. The classification of the responses is performed by using Support Vector Machines (SVM&rsquo / s) and Bayesian decision. These methods are independently applied to the row-column intensification groups of P300 speller to observe the differences in human perception to these two visual stimulation types. It is observed from the investigated datasets that the prediction accuracies in these two groups are different for each subject even for optimum classification parameters. Furthermore, in these datasets, the classification accuracy was improved when the signals are preprocessed with Wiener filtering. With this method, the test characters are predicted with 100% accuracy in 4 trial repetitions in P300 Speller dataset of BCI Competition II. Besides, only 8 trials are needed to predict the target character with the designed BCI system.

Prostate cancer is the most common cancer in men, with the incidence rapidly increasing in Europe over the past two decades. Reliable biomarkers for prostate cancer are currently unavailable. Thus, there is an urgent need for improved biomarkers to diagnose prostate cancer at an early stage and to determine the best treatment options. Higher expression of transforming growth factor-β (TGFβ) has been reported in patients with aggressive cancer. TGFβ is a multifunctional cytokine that acts as a tumor suppressor during early tumor development, and as a tumor promoter at later stages of cancer. TGFβ signals through the canonical Smad or non-Smad cascade via TGFβ type II and type I receptors. The TGFβ signaling cascade is regulated by various post-translational modifications of its key components. The present investigation aimed to identify a potential function of TRAF6 in TGFβ-induced responses in prostate cancer. The first two articles of this thesis unveil the proteolytic cleavage of TGFβ type I receptor (TβRI), and the biological importance of the liberated TβRI intracellular domain (TβRI-ICD) in the nucleus. We found that tumor necrosis factor receptor-associated factor 6 (TRAF6) polyubiquitinates TβRI, which leads to cleavage of TβRI by tumor necrosis factor alpha converting enzyme (TACE) in a protein kinase C zeta (PKCζ)-dependent manner. Following ectodomain shedding, TβRI undergoes a second cleavage by presenilin 1 (PS1), which liberates TβRI-ICD. TβRI-ICD translocates to the nucleus, where it regulates its own expression as well as expression of the pro-invasive gene Snail1, thereby promoting invasion. We further found that TβRI-ICD associates with Notch intracellular domain (NICD) to drive expression of the pro-invasive gene Snail1, as well as Notch1 ligand Jag1. The third article provides evidence that TRAF6 promotes Lys63-linked polyubiquitination of TβRI at Lys178 in a TGFβ-dependent manner. TβRI polyubiquitination was found to be a prerequisite for TβRI nuclear translocation, and thus for regulation of the genes involved in cell cycle, differentiation, and invasion of prostate cancer cells. In the fourth article we investigated the role of the pro-invasive gene Snail1 in TGFβ-induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cells.